N-protected Α-amino Acids Research Articles

Photochemical Deracemization of N-Carboxyanhydrides En Route to Chiral α-Amino Acid Derivatives.

Readily accessible, racemic N-carboxyanhydrides (NCAs) of α-amino acids underwent a deracemization reaction upon irradiation at λ=366 nm in the presence of a chiral benzophenone catalyst. The enantioenriched NCAs (up to 98 % ee) serve as activated α-amino acid surrogates and, due to their instability, they were directly converted into consecutive products. N-Protected α-amino acid esters were obtained after reaction with MeOH and N-benzoylation (14 examples, 70 %-quant., 82-96 % ee). Other consecutive reactions included amide (ten examples, 65 %-quant., 90-98 % ee) and peptide (three examples, 75-89 %, d. r.=97/3 to 94/6) bond formation. Limitations of the method relate for some NCAs to issues with solubility, photooxidation, and high configurational lability.

Microwave-Assisted Synthesis and Characterization of Novel 1,3,4-Oxadiazole Derivatives and Evaluation of In Vitro Antimycobacterial Activity.

Objective The study's goal was to come up with and make a new group of 1,3,4-oxadiazole derivatives (3a-3e) and test how well they could kill Mycobacterium tuberculosis (Mtb) H37Rv strain. Additionally, molecular docking and pharmacokinetic properties were analyzed using computational software to identify potential inhibitors, followed by in vitro antimycobacterial assays. Methods A group of 1,3,4-oxadiazoles was prepared by reacting acyl hydrazides with alanine, an N-protected α-amino acid, and a small amount of POCl3. This was carried out under microwave treatment. The structural characterization of the newly synthesized compounds was performed using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. The in vitro antimycobacterial activity of the 1,3,4-oxadiazole derivatives (3a-3e) was assessed using the microplate Alamar Blue assay against the Mtb H37Rv strain. The synthesized compounds were subjected to molecular docking investigations in order to gain insights into their interaction mechanisms with the mycobacterial enzyme InhA (enoyl-acyl carrier protein reductase). Computational analysis of pharmacokinetic properties was performed to predict the oral bioavailability and drug-likeness of the compounds. Results All synthesized compounds inhibited the growth of Mtbat concentrations of 50 and 100 μg/mL. At a concentration of 50 μg/mL, compounds 3c and 3d exhibited the most prominent antimycobacterial action. Molecular docking results revealed that compound 3d exhibited the highest binding energy interaction with the InhA enzyme (-9.1 kcal/mol). Pharmacokinetic predictions indicated that all compounds possess favorable drug-like properties suitable for oral administration. Conclusion This study successfully synthesized a novel series of oxadiazole derivatives (3a-3e) using a microwave-assisted method with high yields. The synthesized compounds demonstrated significant antimycobacterial activity, particularly compounds 3c and 3d. Molecular docking and pharmacokinetic analyses further confirmed the potential of these compounds as promising leads for the development of anti-tubercular agents.

On-DNA Derivatization of Quinoxalin-2-ones by Visible-Light-Triggered Alkylation with Carboxylic Acids.

An efficient visible-light-induced alkylation of DNA-tagged quinoxaline-2-ones was described. The methodology demonstrated moderate-to-excellent conversions under mild conditions. The reaction was found to be tolerant with both N-protected α-amino acids and aliphatic carboxylic acids and could be applied to the synthesis of focused DNA-encoded quinoxalin-2-one libraries.

Organocatalytic Multicomponent Synthesis of α/β-Dipeptide Derivatives.

A straightforward multicomponent Knoevenagel-aza-Michael-cyclocondensation reaction involving readily available hydroxamic acid-derived from naturally occurring α-amino acids allows a diversity-oriented synthesis of novel isoxazolidin-5-ones possessing an N-protected α-amino acid pendant with good to high diastereoselectivities thanks to a match effect with a chiral organocatalyst. These diversely substituted heterocycles, easily isolated as a single diastereoisomer, proved to be versatile platforms for the formation of an array of α/β-dipeptide fragments.

The Synthesis of α-Aminophosphonates via Enantioselective Organocatalytic Reaction of 1-(N-Acylamino)alkylphosphonium Salts with Dimethyl Phosphite.

α-Aminophosphonic acids are phosphorus analogues of α-amino acids. Compounds of this type find numerous applications in medicine and crop protection due to their unique biological activities. A crucial factor in these activities is the configuration of the stereoisomers. Only a few methods of stereoselective transformation of α-amino acids into their phosphorus analogues are known so far and all of them are based on asymmetric induction, thus involving the use of a chiral substrate. In contrast, we have focused our efforts on the development of an effective method for this type of transformation using a racemic mixture of starting N-protected α-amino acids and a chiral catalyst. Herein, a simple and efficient stereoselective organocatalytic α-amidoalkylation of dimethyl phosphite by 1-(N-acylamino)alkyltriphenylphosphonium salts to enantiomerically enriched α-aminophosphonates is reported. Using 5 mol% of chiral quinine- or hydroquinine-derived quaternary ammonium salts provides final products in very good yields up to 98% and with up to 92% ee. The starting phosphonium salts were easily obtained from α-amino acid derivatives by decarboxylative methoxylation and subsequent substitution with triphenylphosphonium tetrafluoroborate. The appropriate self-disproportionation of enantiomers (SDE) test for selected α-aminophosphonate derivatives via achiral flash chromatography was performed to confirm the reliability of the enantioselectivity results that were obtained.

A Straightforward and High-Yielding Synthesis of 1,2,4-Oxadiazoles from Chiral N-Protected α-Amino Acids and Amidoximes in Acetone-Water: An Eco-Friendly Approach

A straightforward and high-yielding methodology for the synthesis of a high structural diversity of 1,2,4-oxadiazoles from different chiral N-protected α-amino acids and amidoximes under microwave (MW) irradiation is described herein. This greener approach gives the desired products using acetone/water as solvent in very short reaction times.

Catalyst-free Mannich-type reaction of 1-(N-acylamino)alkyltriphenylphosphonium salts with silyl enolates

A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products.

Many fungal quinazolinone metabolites, which contain the methyl-indole pyrazino [1,2-b]quinazoline-3,6-dione core, have been found to possess promising antitumor activity. The purpose of this work was to synthesize the enantiomeric pairs of two members of this quinazolinone family, to explore their potential as antitumor and their ability to revert multidrug resistance. The marine natural product fiscalin B (4c), and antienantiomers (4b, 5b, and 5c) were synthesized via a one-pot approach, while the syn enantiomers (4a, 4d, 5a, and 5d) were synthetized by a multi-step procedure. These strategies used anthranilic acid (i), chiral N-protected α-amino acids (ii), and tryptophan methyl esters (iii) to form the core ring of pyrazino[2,1-b]quinazoline-3,6-dione scaffold. Four enantiomeric pairs, with different enantiomeric purities, were obtained with overall yields ranging from 7 to 40%. Compounds 4a–d and 5a–d were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and 5a–d displayed GI50 values ranging from 31 to 52 μM, which are lower than those of 4a–d. Nevertheless, no effect on P-glycoprotein (P-gp) modulation was observed for all compounds. This study disclosed new data for fiscalin B (4c), as well as for its analogues for a future development of novel anticancer drug leads.

Enamines of 3-acyltetramic acids from β-enamino amides and amino acids

A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-amino acids and subsequent cyclisation of the obtained intermediates in refluxing TFA. The tetramic derivatives are obtained with very good enantiopurity (e.r. ≥95:5). Ring-enlarged analogues (piperidine-2,4-diones) can also be obtained from β-amino acids.

Synthesis of Chiral TFA-Protected α-Amino Aryl-Ketone Derivatives with Friedel-Crafts Acylation of α-Amino Acid N-Hydroxysuccinimide Ester.

Chiral N-protected α-amino aryl-ketones are one of the useful precursors used in the synthesis of various biologically active compounds and can be constructed via Friedel–Crafts acylation of N-protected α-amino acids. One of the drawbacks of this reaction is the utilization of toxic, corrosive and moisture-sensitive acylating reagents. In peptide construction via amide bond formation, N-hydroxysuccinimide ester (OSu), which has high storage stability, can react rapidly with amino components and produces fewer side reactions, including racemization. This study reports the first synthesis and utilization of N-trifluoroacetyl (TFA)-protected α-amino acid-OSu as a potential acyl donor for Friedel–Crafts acylation into various arenes. The TFA-protected isoleucine derivative and its diastereomer TFA-protected allo-isoleucine derivative were investigated to check the retention of α-proton chirality in the Friedel–Crafts reaction. Further utilization of OSu in other branched-chain and unbranched-chain amino acids results in an adequate yield of TFA-protected α-amino aryl-ketone without loss of optical purity.

Visible light photocatalytic decarboxylative monofluoroalkenylation of α-amino acids with gem-difluoroalkenes.

α-Amino acids are among the most common biologically active molecules in nature, and their functionalization has attracted much attention. In this communication, a novel, efficient and general visible-light photocatalytic decarboxylative monofluoroalkenylation of N-protected α-amino acids with gem-difluoroalkenes is reported, affording the corresponding α-amino monofluoroalkenes which might find applications in medical chemistry and materials science. The reaction proceeded at room temperature with high efficiency and tolerance of various functional groups.

Synthesis and enantiomeric recognition studies of optically active 5,5-dioxophenothiazine bis(urea) and bis(thiourea) derivatives

Novel optically active 5,5-dioxophenothiazine bis(urea) and bis(thiourea) derivatives were synthesized and their enantiomeric recognition abilities toward the enantiomers of tetrabutylammonium salts of α-hydroxy and N-protected α-amino acids were examined in acetonitrile using fluorescence spectroscopy.

ChemInform Abstract: One‐Pot Synthesis of Amides from Carboxylic Acids Activated Using Thionyl Chloride.

A one-pot synthesis of secondary and tertiary amides from carboxylic acids and amines by using SOCl2 has been developed. Also when sterically hindered amines were used as the starting materials, excellent yields of the corresponding amides were obtained. The amidation of N-protected α-amino acids with secondary amines proceeds effectively with good yields. The process works well also in the presence of acid sensitive groups and occurs with almost complete retention of stereochemical integrity of chiral substrates. This protocol could be extended to industrial large-scale production processes.

Origin of problems related to Staudinger reduction in carbopeptoid syntheses.

We report the solid phase synthesis of -GG-X-GG- type α/β-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc derivative (e.g., Fmoc-RibAFU(ip)-OH) and the azido derivative (e.g., N3-RibAFU(ip)-OH) via Staudinger reaction with nBu3P can be successfully applied. Both X-ray diffraction, 1H- and 31P-NMR, and theoretical (QM) data support and explain why the application of Ph3P as Staudinger reagent is "ineffective" in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (-CONH-) bond. The failure of the polypeptide chain elongation with N3-cX originates from the "coincidence" of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack during the hydrolysis of a quasi penta-coordinated triphenylphosphinimine. Nevertheless, the synthesis of the above α/β-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo- and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts.

Installing amino acids and peptides on N-heterocycles under visible-light assistance.

Readily available natural α-amino acids are one of nature’s most attractive and versatile building blocks in synthesis of natural products and biomolecules. Peptides and N-heterocycles exhibit various biological and pharmaceutical functions. Conjugation of amino acids or peptides with N-heterocycles provides boundless potentiality for screening and discovery of diverse biologically active molecules. However, it is a great challenge to install amino acids or peptides on N-heterocycles through formation of carbon-carbon bonds under mild conditions. In this article, eighteen N-protected α-amino acids and three peptides were well assembled on phenanthridine derivatives via couplings of N-protected α-amino acid and peptide active esters with substituted 2-isocyanobiphenyls at room temperature under visible-light assistance. Furthermore, N-Boc-proline residue was successfully conjugated with oxindole derivatives using similar procedures. The simple protocol, mild reaction conditions, fast reaction, and high efficiency of this method make it an important strategy for synthesis of diverse molecules containing amino acid and peptide fragments.

Dual Catalytic Decarboxylative Allylations of α-Amino Acids and Their Divergent Mechanisms.

The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.

Synthesis and enantiomeric recognition studies of optically active acridone bis(urea) and bis(thiourea) derivatives

Novel optically active acridone bis(urea) and bis(thiourea) derivatives were synthesized and their enantiomeric recognition abilities towards the enantiomers of tetrabutylammonium salts of α-hydroxy and N-protected α-amino acids were examined in acetonitrile–DMSO 99:1 using fluorescence spectroscopy.

Racemization-Free Synthesis of Morpholinone Derivatives from α-Amino Acids

A simple strategy is reported for the synthesis of chiral N-protected morpholinone derivatives by a base (potassium carbonate)-mediated cyclization reaction of N-protected α-amino acids with 1,2-dibromoethane. The morpholinone derivatives are obtained in good yields and in enantiomerically pure forms.

ChemInform Abstract: Solvent‐Free Reduction of Carboxylic Acids to Alcohols with NaBH4 Promoted by 2,4,6‐Trichloro‐1,3,5‐triazine and PPh3 in the Presence of K2CO3.

A simple, rapid, and eco-friendly method for NaBH4 reduction of carboxylic acids to alcohols under solvent-free conditions was developed using a combination of 2,4,6-trichloro-1,3,5-triazine (TCT) with a catalytic amount of triphenylphosphine as an acid activator. With the 1 : 0.2 : 1.5 : 2 mole ratio of TCT : PPh3 : K2CO3 : NaBH4, carboxylic acids including aromatic acids, aliphatic acids, and N-protected α-amino acids (Fmoc, Z) could readily undergo reduction to give the corresponding alcohols in good to excellent yields within 10 min.

A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H.

N-Protected amino acids can be easily converted into chiral α-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity.